Axially Chiral Nonbenzenoid Nanographene with Second Harmonic Generation Property.

Chiral nanographenes (NGs) have garnered significant interest as optoelectronic materials in recent years. While helically chiral NGs have been extensively studied, axially chiral NGs have only witnessed limited examples, with no prior reports of axially chiral nonbenzenoid NGs. Herein we report an axially chiral nonbenzenoid nanographene featuring six pentagons and four heptagons. This compound, denoted as 2, was efficiently synthesized via an efficient Pd-catalyzed aryl silane homocoupling reaction. The presence of two bulky 3,5-di-tert-butylphenyl groups around the axis connecting the two nonbenzenoid PAH (AHR) segments endows 2 with atropisomeric chirality and high racemization energy barrier, effectively preventing racemization of both R- and S-enantiomers at room temperature. Optically pure R-2 and S-2 were obtained by chiral HPLC separation, and they exhibit circular dichroism (CD) activity at wavelengths up to 660 nm, one of the longest wavelengths with CD responses reported for the chiral NGs. Interestingly, racemic 2 forms a homoconfiguration π-dimer in the crystal lattice, belonging to the I222 chiral space group. Consequently, this unique structure renders crystals of 2 with a second harmonic generation (SHG) response, distinguishing it from all the reported axially chiral benzenoid NGs. Moreover, R-2 and S-2 also exhibit SHG-CD properties.

Novel Dissymmetric Formal Quinoidal Molecules End-Capped by Dicyanomethylene and Triphenylphosphonium.

A number of quinoidal molecules with symmetric end-capping groups, particularly dicyanomethylene units, have been synthesized for organic optoelectronic materials. In comparison, dissymmetric quinoidal molecules, characterized by end-capping with different groups, are less explored. In this paper, we present the unexpected formation of new formal quinoidal molecules, which are end-capped with both dicyanomethylene and triphenylphosphonium moieties. The structures of these dissymmetric quinoidal molecules were firmly verified by single crystal structural analyses. On the basis of the control experiments and DFT calculations, we proposed the reaction mechanism for the formation of these dissymmetric quinoidal molecules. The respective zwitterionic forms should make contributions to the ground state structures of these quinoidal molecules based on the analysis of their bond lengths and aromaticity and Mayer Bond Orbital (MBO) calculation. This agrees well with the fact that negative solvatochromism was observed for these quinoidal molecules. Although these new quinoidal molecules are non-emissive both in solutions and crystalline states, they become emissive with quantum yields up to 51.4 % after elevating the solvent viscosity or dispersing them in a PMMA matrix. Interestingly, their emissions can also be switched on upon binding with certain proteins, in particular with human serum albumin.

3-Nitroindoles Serving as N-Centered Nucleophiles for Aza-1,6-Michael Addition to para-Quinone Methides.

An unprecedented N-alkylation of 3-nitroindoles with para-quinone methides was developed for the first time. Using potassium carbonate as the base, a wide range of structurally diverse N-diarylmethylindole derivatives were obtained with moderated to good yields via the protection group migration/aza-1,6-Michael addition sequences. The reaction process was also demonstrated by control experiments. Different from the previous advances where 3-nitrodoles served as electrophiles trapping by various nucleophiles, the reaction herein is featured that 3-nitrodoles is defined with latent N-centered nucleophiles to react with ortho-hydrophenyl p-QMs for construction of various N-diarylmethylindoles.

A Heptacene Analogue Entailing a Quinoidal Benzodi[7]annulene (7/6/7 Ring) Core with a Tunable Configuration and Multiple Redox Properties.

Non-benzenoid acenes containing heptagons have received increasing attention. We herein report a heptacene analogue containing a quinoidal benzodi[7]annulene core. Derivatives of this new non-benzenoid acene were obtained through an efficient synthetic strategy involving an Aldol condensation and a Diels-Alder reaction as key steps. The configuration of this heptacene analogue can be modulated from a wavy to a curved one by just varying the substituents from a (triisopropylsilyl)ethynyl group to a 2,4,6-triisopropylphenyl (Trip) group. When mesityl (Mes) groups are linked to the heptagons, the resulting non-benzenoid acene displays polymorphism with a tunable configuration from a curved to a wavy one upon varying the crystallization conditions. In addition, this new non-benzenoid acene can be oxidized or reduced by NOSbF6 or KC8 to the respective radical cation or radical anion. Compared with the neutral acene, the radical anion shows a wavy configuration and the central hexagon becomes aromatic.

Diazulenorubicene as a Non-benzenoid Isomer of peri-Tetracene with Two Sets of 5/7/5 Membered Rings Showing Good Semiconducting Properties.

Non-benzenoid polycyclic aromatic hydrocarbons (PAHs) have received a lot of attention because of their unique optical, electronic, and magnetic properties, but their synthesis remains challenging. Herein, we report a non-benzenoid isomer of peri-tetracene, diazulenorubicene (DAR), with two sets of 5/7/5 membered rings synthesized by a (3+2) annulation reaction. Compared with the precursor containing only 5/7 membered rings, the newly formed five membered rings switch the aromaticity of the original heptagon/pentagon from antiaromatic/aromatic to non-aromatic/antiaromatic respectively, modify the intermolecular packing modes, and lower the LUMO levels. Notably, compound 2 b (DAR-TMS) shows p-type semiconducting properties with a hole mobility up to 1.27 cm2  V-1 s-1 . Moreover, further extension to larger non-benzenoid PAHs with 19 rings was achieved through on-surface chemistry from the DAR derivative with one alkynyl group.

Development and validation of a nomogram for early assessment the severity of acute pancreatitis.

BACKGROUND: Acute pancreatitis is an acute inflammatory disorder of the pancreas, and severe acute pancreatitis is associated with high mortality. Early assessment the severity of AP has an important significance for improving clinical outcomes. Our object aimed to develop a nomogram with high simplicity and rapidity for predicting the severity of acute pancreatitis. METHODS: Patients admitted to the Hunan Provincial People's Hospital within 72 h from onset of AP from January 2010 and December 2020 were enrolled to establish a nomogram. Independent predictors were determined using univariate and multivariate analysis and then assembled to construct a predicting nomogram. The performance of proposed nomogram was evaluated by Brier score and Harrell's concordance index (C-index). Meanwhile, clinical data of AP patients from January 2021 to January 2022 were collected for external validation. RESULTS: Album (OR 0.891, 95%CI 0.867-0.917), calcium (OR 0.151, 95%CI 0.084-0.273), neutrophil to lymphocyte ratio (OR 1.055, 95%CI 1.023-1.088) and systemic inflammatory response syndrome (OR 6.292, 95%CI 4.459-8.879) were identified as independent factors of SAP after univariate and multivariate analysis (p < .05). A predictive nomogram was accordingly established using these four independent variables. The internally verified C-index was 0.796 (95% CI 0.773-0.818), Brier score was 0.138. The externally verified C index was 0.820 (95% CI 0.754-0.887). CONCLUSION: A nomogram for predicting the severity of AP was well developed, it may be of great significance for clinicians to quickly assess the progress of AP and choose more-targeted strategies.

Identification of HMGCR as the anticancer target of physapubenolide against melanoma cells by in silico target prediction.

Physapubenolide (PB), a withanolide-type compound extracted from the traditional herb Physalis minima L., has been demonstrated to exert remarkable cytotoxicity against cancer cells; however, its molecular mechanisms are still unclear. In this study, we demonstrated that PB inhibited cell proliferation and migration in melanoma cells by inducing cell apoptosis. The anticancer activity of PB was further verified in a melanoma xenograft model. To explore the mechanism underlying the anticancer effects of PB, we carried out an in silico target prediction study, which combined three approaches (chemical similarity searching, quantitative structure-activity relationship (QSAR), and molecular docking) to identify the targets of PB, and found that PB likely targets 3-hydroxy-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, which promotes cancer cell proliferation, migration, and metastasis. We further demonstrated that PB interacted with HMGCR, decreased its protein expression and inhibited the HMGCR/YAP pathway in melanoma cells. In addition, we found that PB could restore vemurafenib sensitivity in vemurafenib-resistant A-375 cells, which was correlated with the downregulation of HMGCR. In conclusion, we demonstrate that PB elicits anticancer action and enhances sensitivity to vemurafenib by targeting HMGCR.

Tuning Proapoptotic Activity of a Phosphoric-Acid-Tethered Tetraphenylethene by Visible-Light-Triggered Isomerization and Switchable Protein Interactions for Cancer Therapy.

We herein report a phosphoric-acid-substituted tetraphenylethene (T-P) capable of adapting its geometric configuration and biological activity to the microenvironment upon light irradiation for apoptosis modulation. Different from most ultraviolet-responsive isomerization, T-P undergoes cis-trans isomerization under visible light irradiation, which is biocompatible and thus photo-modulation is possible in living biosystems. By using alkaline phosphatase (ALP) and albumin as dual targets, T-P isomers display different protein binding selectivity, cancer-cell internalization efficiency and apoptosis-inducing ability. The proapoptotic activity was found to be kinetically controlled by the enzymatic reaction with ALP and regulated by co-existing albumin. Motivated by these findings, two-way modulation of proapoptotic effect and on-demand boosting anticancer efficacy were realized in vitro and in vivo using light and endogenous proteins as multiple non-invasive switching stimuli.

Inhibition of AXL enhances chemosensitivity of human ovarian cancer cells to cisplatin via decreasing glycolysis.

Anexelekto (AXL), a member of the TYRO3-AXL-MER (TAM) family of receptor tyrosine kinases (RTK), is overexpressed in varieties of tumor tissues and promotes tumor development by regulating cell proliferation, migration and invasion. In this study, we investigated the role of AXL in regulating glycolysis in human ovarian cancer (OvCa) cells. We showed that the expression of AXL mRNA and protein was significantly higher in OvCa tissue than that in normal ovarian epithelial tissue. In human OvCa cell lines suppression of AXL significantly inhibited cell proliferation, and increased the sensitivity of OvCa cells to cisplatin, which also proved by nude mice tumor formation experiment. KEGG analysis showed that AXL was significantly enriched in the glycolysis pathways of cancer. Changes in AXL expression in OvCa cells affect tumor glycolysis. We demonstrated that the promotion effect of AXL on glycolysis was mediated by phosphorylating the M2 isoform of pyruvate kinase (PKM2) at Y105. AXL expression was significantly higher in cisplatin-resistant OvCa cells A2780/DDP compared with the parental A2780 cells. Inhibition of AXL decreased the level of glycolysis in A2780/DDP cells, and increased the cytotoxicity of cisplatin against A2780/DDP cells, suggesting that AXL-mediated glycolysis was associated with cisplatin resistance in OvCa. In conclusion, this study demonstrates for the first time that AXL is involved in the regulation of the Warburg effect. Our results not only highlight the clinical value of targeting AXL, but also provide theoretical basis for the combination of AXL inhibitor and cisplatin in the treatment of OvCa.

Chemometric QSAR modeling of acute oral toxicity of Polycyclic Aromatic Hydrocarbons (PAHs) to rat using simple 2D descriptors and interspecies toxicity modeling with mouse.

The information of the acute oral toxicity for most polycyclic aromatic hydrocarbons (PAHs) in mammals are lacking due to limited experimental resources, leading to a need to develop reliable in silico methods to evaluate the toxicity endpoint. In this study, we developed the quantitative structure-activity relationship (QSAR) models by genetic algorithm (GA) and multiple linear regression (MLR) for the rat acute oral toxicity (LD50) of PAHs following the strict validation principles of QSAR modeling recommended by OECD. The best QSAR model comprised eight simple 2D descriptors with definite physicochemical meaning, which showed that maximum atom-type electrotopological state, van der Waals surface area, mean atomic van der Waals volume, and total number of bonds are main influencing factors for the toxicity endpoint. A true external set (554 compounds) without rat acute oral toxicity values, and 22 limit test compounds, were firstly predicted along with reliability assessment. We also compared our proposed model with the OPERA predictions and recently published literature to prove the prediction reliability. Furthermore, the interspecies toxicity (iST) models of PAHs between rat and mouse were also established, validated and employed for filling data gap. Overall, our developed models should be applicable to new or untested or not yet synthesized PAHs falling within the applicability domain (AD) of the models for rapid acute oral toxicity prediction, thus being important for environmental or personal exposure risk assessment under regulatory frameworks.

Dicyclohepta[ijkl,uvwx]rubicene with Two Pentagons and Two Heptagons as a Stable and Planar Non-benzenoid Nanographene.

Polycyclic aromatic hydrocarbons with hexagons/pentagons or hexagons/heptagons have been intensively investigated in recent years, but those with simultaneous presence of hexagons, pentagons and heptagons remain rare. In this paper, we report dicyclohepta[ijkl,uvwx]rubicene (DHR), a non-benzenoid isomer of dibenzo[bc,kl]coronene with two pentagons and two heptagons. We developed an efficient and scalable synthetic method for DHR by using Scholl reaction and dehydrogenation. Crystal structure of DHR shows that the benzenoid rings, two pentagons and two heptagons are coplanar. The bond lengths analysis and the ICSS(1)zz and LOL-π calculations indicate that the incorporation of two formal azulene moieties has an effect on the conjugated structure. The π-electrons of benzenoid and pentagon rings are more delocalized. Cyclic voltammetry studies indicate that DHR shows multiple oxidation and reduction potentials. Interestingly, DHR exhibits unusual S0 to S2 absorption and abnormal anti-Kasha S2 to S0 emission. Moreover, crystals of DHR exhibit semiconducting behaviour with hole mobility up to 0.082 cm2 V-1 s-1 .

Eukaryotic elongation factor-2 kinase regulates the cross-talk between autophagy and pyroptosis in doxorubicin-treated human melanoma cells in vitro.

Eukaryotic elongation factor-2 kinase (eEF-2K), a negative regulator of protein synthesis, has been shown to play an important role in modulating autophagy and apoptosis in tumor cells under various stresses. In this study, we investigated the regulatory role of eEF-2K in pyroptosis (a new form of programmed necrosis) in doxorubicin-treated human melanoma cells. We found that doxorubicin (0.5-5 µmol/L) induced pyroptosis in melanoma cell lines SK-MEL-5, SK-MEL-28, and A-375 with high expression of DFNA5, but not in human breast cancer cell line MCF-7 with little expression of DFNA5. On the other hand, doxorubicin treatment activated autophagy in the melanoma cells; inhibition of autophagy by transfecting the cells with siRNA targeting Beclin1 or by pretreatment with chloroquine (20 µmol/L) significantly augmented pyroptosis, thus sensitizing the melanoma cells to doxorubicin. We further demonstrated that doxorubicin treatment activated eEF-2K in the melanoma cells, and silencing of eEF-2K blunted autophagic responses, but promoted doxorubicin-induced pyroptotic cell death. Taken together, the above results demonstrate that eEF-2K dictates the cross-talk between pyroptosis and autophagy in doxorubicin-treated human melanoma cells; suppression of eEF-2K results in inhibiting autophagy and augmenting pyroptosis, thus modulating the sensitivity of melanoma cells to doxorubicin, suggesting that targeting eEF-2K may reinforce the antitumor efficacy of doxorubicin, offering a new insight into tumor chemotherapy.

Tubeimoside-1, a triterpenoid saponin, induces cytoprotective autophagy in human breast cancer cells in vitro via Akt-mediated pathway.

Autophagy, a form of cellular self-digestion by lysosome, is associated with various disease processes including cancers, and modulating autophagy has shown promise in the treatment of various malignancies. A number of natural products display strong antitumor activity, yet their mechanisms of action remain unclear. To gain a better understanding of how traditional Chinese medicine agents exert antitumor effects, we screened 480 natural compounds for their effects on autophagy using a high content screening assay detecting GFP-LC3 puncta in HeLa cells. Tubeimoside-1 (TBMS1), a triterpenoid saponin extracted from Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), was identified as a potent activator of autophagy. The activation of autophagy by TBMS1 was evidenced by increased LC3-II amount and GFP-LC3 dots, observation of autophagosomes under electron microscopy, and enhanced autophagic flux. To explore the mechanisms underlying TBMS1-activated autophagy, we performed cheminformatic analyses and surface plasmon resonance (SPR) binding assay that showed a higher likelihood of the binding between Akt protein and TBMS1. In three human breast cancer cell lines, we demonstrated that Akt-mTOR-eEF-2K pathway was involved in TBMS1-induced activation of autophagy, while Akt-mediated downregulations of Mcl-1, Bcl-xl, and Bcl-2 led to the activation of apoptosis of the breast cancer cells. Inhibition of autophagy enhanced the cytotoxic effect of TBMS1 via promoting apoptosis. Our results demonstrate the role and mechanism of TBMS1 in activating autophagy, suggesting that inhibition of cytoprotective autophagy may act as a therapeutic strategy to reinforce the activity of TBMS1 against cancers.

Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect.

Tumor cells rely mainly on glycolysis for energy production even in the presence of sufficient oxygen, a phenomenon termed the Warburg effect, which is the most outstanding characteristic of energy metabolism in cancer cells. This metabolic adaptation is believed to be critical for tumor cell growth and proliferation, and a number of onco-proteins and tumor suppressors, including the PI3K/Akt/mTOR signaling pathway, Myc, hypoxia-inducible factor and p53, are involved in the regulation of this metabolic adaptation. Moreover, glycolytic cancer cells are often invasive and impervious to therapeutic intervention. Thus, altered energy metabolism is now appreciated as a hallmark of cancer and a promising target for cancer treatment. A better understanding of the biology and the regulatory mechanisms of aerobic glycolysis has the potential to facilitate the development of glycolysis-based therapeutic interventions for cancer. In addition, glycolysis inhibition combined with DNA damaging drugs or chemotherapeutic agents may be effective anticancer strategies through weakening cell damage repair capacity and enhancing drug cytotoxicity.

[Screening and validation of long non-coding RNAs in brain tissue of inflammation-induced preterm mice].

OBJECTIVE: To investigate the association between long non-coding RNAs (lncRNAs) and brain injury in inflammation-induced preterm mice, and to provide a reference for the prevention and treatment of brain injury. METHODS: An intraperitoneal injection of lipopolysaccharide in pregnant mice was performed to establish a model of inflammation-induced preterm mice with brain injury (preterm group). The full-term mice delivered by normal pregnant mice were used as controls (full-term group). The lncRNA chip assay was used to screen out the lncRNAs associated with brain injury in preterm mice. Quantitative real-time PCR was used to validate the lncRNAs identified by the above method. RESULTS: The preterm and full-term groups showed significant differences in the expression of 1 978 lncRNAs (P<0.05), consisting of 786 up-regulated lncRNAs and 1 192 down-regulated lncRNAs, and 29 lncRNAs were 1.5 or more times differentially expressed between the two groups. A further analysis was performed for the 10 most differentially expressed lncRNAs, and the results showed that these lncRNAs were involved in the biological processes including transcription, signal transduction, apoptosis, cell cycle, and inflammatory response, as well as G protein-coupled receptor signaling pathway and neuropeptide signaling pathway. Real-time PCR was performed to validate the expression of two lncRNAs in brain tissue in the preterm and full-term groups, and the results were consistent with those of the chip assay. CONCLUSIONS: The expression profiles of lncRNAs in brain tissue change significantly in inflammation-induced preterm mice, and the G protein-coupled receptor signaling pathway may be involved in the pathogenesis of preterm brain injury.

Group Exchange between Ketones and Carboxylic Acids through Directing Group Assisted Rh-Catalyzed Reorganization of Carbon Skeletons.

The Rh(I)-catalyzed direct reorganization of organic frameworks and group exchanges between carboxylic acids and aryl ketones was developed with the assistance of directing group. Biaryls, alkenylarenes, and alkylarenes were produced in high efficiency from aryl ketones and the corresponding carboxylic acids by releasing the other molecule of carboxylic acids and carbon monoxide. A wide range of functional groups were well compatible. The exchanges between two partners were proposed to take place on the Rh-(III) center of key intermediates, supported by experimental mechanistic studies and computational calculations. The transformation unveiled the new catalytic pathway of the group transfer of two organic molecules.

Synthesis of dibenzo[c,e]oxepin-5(7H)-ones from benzyl thioethers and carboxylic acids: rhodium-catalyzed double C-H activation controlled by different directing groups.

A rhodium(III)-catalyzed cross-coupling of benzyl thioethers and aryl carboxylic acids through the two directing groups is reported. Useful structures with diverse substituents were efficiently synthesized in one step with the cleavage of four bonds (CH, CS, OH) and the formation of two bonds (CC, CO). The formed structure is the privileged core in natural products and bioactive molecules. This work highlights the power of using two different directing groups to enhance the selectivity of a double CH activation, the first of such examples in cross-oxidative coupling.

Direct borylation of primary C-H bonds in functionalized molecules by palladium catalysis.

Organoborane compounds are among the most commonly employed intermediates in organic synthesis and serve as crucial precursors to alcohols, amines, and various functionalized molecules. A simple palladium-based system catalyzes the conversion of primary C(sp(3) )H bonds in functionalized complex organic molecules into alkyl boronate esters. Amino acids, amino alcohols, alkyl amines, and a series of bioactive molecules can be functionalized with the use of readily available and removable directing groups in the presence of commercially available additives, simple ligands, and oxygen (O2 ) as the terminal oxidant. This approach represents an economic and environmentally friendly method that could find broad applications.

Controllable Mono-/Dialkenylation of Benzyl Thioethers through Rh-Catalyzed Aryl C-H Activation.

Under solvent control: Benzyl thioethers were alkenylated in excellent yields with broad substrate scope and the selectivity (mono- vs. disubstituted product) was controlled by the solvent and ratio of reactants. Sequential alkenylation with two different alkenes was also carried out in a one-pot process. In addition, the thioether directing group was removed in a one-pot process with simultaneous hydrogenation of the double bond to give the toluene derivatives.

Synthesis of dibenzopyranones through palladium-catalyzed directed C-H activation/carbonylation of 2-arylphenols.

Dibenzopyranones were synthesized by a palladium-catalyzed phenol-directed C-H activation/carbonylation of 2-phenylphenol derivatives in the presence of CO. Pd(OAc)2 was used as a catalyst and Cu(OAc)2 as a catalytic oxidant in the presence of air.